lithium 3-((3,4-dicyanophenyl)sulfonyl)propane-1-sulfonate)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert review and assesment

Adequacy of study:

supporting study

Reliability:

other: Not assignable as result is from expert asessment.

Data source

Reference

Reference Type:

other: Internal Company Report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Assessment of toxicokinetic behaviour of the substance derived from available data as required by REACH Annex VIII section 8.8

Deviations:

not applicable

Principles of method if other than guideline:

Expert review.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Automatically generated during migration to IUCLID 6, no data available

IUPAC Name:

Automatically generated during migration to IUCLID 6, no data available

Test material form:

other: tudy undertaken as expert review of available data which is based on test material in powder form.

Results and discussion

Any other information on results incl. tables

INFORMATION BASED ON PHYSICO-CHEMICAL PROPERTIES

 

The test substance is a lithium salt of a phthalonitrile derivative with a molecular weight of 320 as the lithium salt. It is an involatile solid at room temperature and has a melting point of > 300°C. The substance is very soluble in water (> 25% w/w at 25°C). The log P_owis -3.09 suggesting that the substance is of very limited solubility in lipids. 

 

In its solid form the test substance is a fine powder of which 52.4% of the particles are inhalable (particle size <100 µm) and 4.39 x 10^-2% are respirable (particle size < 5.5 µm).

 

The test substance is hydrolytically stable at pH 4 and pH 7 at 50°C giving an estimated half-life of > 1 year at 25°C, however, at pH 9 it undergoes rapid hydrolysis and shows 99.5% hydrolysis after five days at 50°C. Two main hydrolysis products are produced which are believed to bestructurally similar to the test substance.

 

ABSORPTION, DISTRIBUTION AND EXCRETION

 

 

Absorption

 

Potential for Absorption

 

The test substance in solid form contains 52.4% particles of a size that could be inhaled following exposure to airborne dusts. However as < 0.1% of particles are respirable, little of an in haled dose will reach the alveoli and most of the dose can be expected to be transferred to the stomach via mucocilliary action and swallowing.

 

The test substance is a relatively low molecular weight molecule and therefore its size is unlikely to present a significant barrier to absorption across the gastrointestinal mucosa, hence, uptake as it passes through the gastrointestinal tract may occur. Uptake is likely to vary as it passes through the gut given that it will be ionised to differing degrees at the different pH’s encountered in the gastrointestinal tract. The test substance has a very low log P value and therefore the unionised form is likely to be inhibited from passage across membranes due to a lack of lipid solubility. It is unlikely that active transport mechanisms will be a significant uptake route due to a lack of similarity with endogenous molecules; however, the test substanceis a salt and will release lithium ions which will compete with sodium ions for uptakevia sodium pumps. 

 

Overall, it can be expected that absorption of the intact molecule across the gastrointestinal mucosa will occur, but a proportion of an oral dose is likely to not be absorbed and subsequently be excreted in the faeces.

 

The test substance undergoes limited hydrolysis at pHs of 4 and 7 with less than 10% hydrolysis occurring after 5 days at 50°C, equivalent to a half-life greater than 1 year at 25°C. However, at pH 9 after 5 days at 50 °C almost 100% hydrolysis occurs. Based on the hydrolysis results, it is possible that following oral administration, at least a degree of hydrolysis of the test substance might occur in the lower intestine where up toca.pH 8 could be encountered.

 

The hydrolysis products are expected to be less lipophilic than the test substance which may alter the absorption profile; however, given the structural similarity of the products to the test susbtance, it is expected that overall they will have a similar absorption profile to the parent molecule.

 

Evidence for Absorption

 

An oral repeated dose reproductive developmental toxicity screening study has been conducted on the test substance using doses of 30, 300 and 500 mg/kg/bw/day. Some transient treatment related effects were seen at 500 mg/kg/bw/day such as impairment of body weight in both sexes along with minimal disruption in blood chemistry in females. There was also a nominal effect on adrenal weight in all treated females that may have had an associated histopathological relationship. These findings were not considered toxicologically significant; however, they do provide evidence that the test substance and/or its metabolites/hydrolysis products can be absorbed to a degree sufficient to exert effects. 

 

There is no information on which to determine for certain whether the test substance can be absorbed significantly via dermal exposure. Given its molecular weight it is conceivable that a dermal absorption could occur; however, factors such as it low lipid solubility are likely to mean that absorption by this route is unlikely to be significant.

 

 

DISTRIBUTION

 

It is very unlikely that the test substance will exhibit any significant distribution within the body between plasma and tissues. The substance is a salt and on dissolution will form an anion and a lithium cation. The anion is polar and therefore it is unlikely to distribute to any significant extent in the body. The lithium cation is likely to compete with sodium for uptake via sodium pumps and ultimately it is likely to be incorporated into the body sodium pool. If not replenished, the lithium will be lost over time via normal excretion processes.

 

As no reproductive effects were seen in the oral repeated dose reproductive developmental toxicity screening study it is not possible to draw any conclusions about whether the distribution of the test substance in the body can include the reproductive organs.   

 

 

METABOLISM

 

The test substance contains a water solubilising sulphonic acid and two cyano groups which are likely to aid metabolism of the molecule by the cytochrome P450 enzyme metabolising system. The sulphonic acid group is also likely to aid excretion of the molecule.

 

In an in vitro bacterial reverse mutation assay using S. typhimurium and E.coli the test substance did not induce any significant increases in observed numbers of revertant colonies. The test substance gave a negative result in an in vivo Mouse Micronucleus Test. Given the negative results, no conclusions about the potential of the test substance to undergo metabolic change can be drawn from these studies.

 

In an in vitro mammalian chromosome aberration assay in human lymphocytes, the test substance was considered to be clastogenic following 24-hours of continuous exposure in the absence of metabolic activation (rat liver homogenate (S9)). It was negative in the presence of S9 and this may indicate that the test substance can undergo metabolism in the liver and possibly other organs.  

 

Excretion

 

The main route of excretion of absorbed test substance and/or its metabolites is likely to be via the kidneys into the urine. The molecular weight of the test substance is below the biliary exclusion limit of circa 325 in the rat and 500 in humans and therefore elimination of any absorbed substance in the bile is not expected to be significant. 

 

The lithium ions from the test substance can be expected to be excreted in urine.

 

 

CONCLUSION

 

An assessment of the potential absorption of the test substance based on its physico-chemical properties suggest that absorption across thegastrointestinal mucosa is likely to be slow and part of an oral dose can be expected to be excreted in the faeces. However, a proportion is systemically absorbed as demonstrated by the observation of transient treatment related effects in a repeated dose reproductive developmental toxicity screening study. 

 

There is evidence that the test substance can be metabolised by liver S9. The presence of sulphonic acid and cyano groups on its structure can be expected to aid metabolism of systemically, absorbed test substance to water soluble products that will ultimately be excreted via the kidneys. There is no expectation that the test substance will preferentially distribute to particular organs or tissues in the body.

 

 

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: No bioaccumulation potential based on expert review of available data.
A proportion of the test substance is likely to be systemically absorbed but likely to be subject to metabolism via sulphonic acid and cyano groups on its structure. Ultimately, it is expected to be excreted via the kidneys. There is no expectation that the test susbstance will preferentially distribute to particular organs or tissues in the body.

Executive summary:

Introduction

An expert review of the toxicokinetic profile of the test substance was undertaken based on physicochemical profile and available toxicity data.

Conclusion

An assessment of the potential absorption of the test substance based on its physico-chemical properties suggest that absorption across thegastrointestinal mucosa is likely to be slow and part of an oral dose can be expected to be excreted in the faeces. However, a proportion is systemically absorbed as demonstrated by the observation of transient treatment related effects in a repeated dose reproductive developmental toxicity screening study. 

 

There is evidence from an in vitro mammalian chromosome aberration test that the test substance can be metabolised by liver S9. The presence of sulphonic acid and cyano groups on its structure can be expected to aid metabolism of systemically, absorbed test substance to water soluble products that will ultimately be excreted via the kidneys. There is no expectation that the test substance will preferentially distribute to particular organs or tissues in the body.